Systemic treatment of neuroendocrine tumors with hepatic metastases

Neuroendocrine tumors, 1-2% of all malignancies, are relatively slow-growing neoplasms. The majority of neuroendocrine tumors belong to the World Health Organization Group 2 with well-differentiated endocrine carcinomas, but some tumors can be aggressive. The most common are gastroenteropancreatic-neuroendocrine tumors, followed by bronchopulmonary neuroendocrine tumors; less frequent locations are the ovaries, testis and hepatobiliary locations. They can be either non-functioning tumors with symptoms related to mass effects and malignant tumor disease or functioning tumors with specific hormones/neuropeptides autonomously secreted to induce specific clinical syndromes. Localized neuroendocrine tumors are less frequent than metastatic ones; in fact, up to 75% of patients with small bowel neuroendocrine tumors and 30-85% of pancreatic neuroendocrine tumors present with liver metastases either at the time of diagnosis or during the course of the disease. The predominant metastatic site is the liver, which is the best prognostic marker of survival regardless of the primary site. If surgical resection or interventional therapies of the hepatic tumor burden are not feasible, or if the metastases are not confined to the liver, systemic treatment remains the only option. None of the systemic therapies is liver-specific, but rather acts on all metastatic sites. The lack of prospective studies comparing different treatment modalities in homogeneous cohorts of patients makes the best treatment strategy poorly defined. Standard systemic therapy options are somatostatin analogues (octreotide and lanreotide), interferon-α and chemotherapy. Somatostatin analogues not only control symptoms related to functioning tumors but tumor growth as well. Because of the studies challenging its efficacy, as well as the potential for side effects, the more widespread acceptance of interferon-α in the treatment of metastatic neuroendocrine tumors has been limited. Well-differentiated neuroendocrine tumors do not show high sensitivity to chemotherapy because of their low mitotic rates, high levels of antiapoptotic protein bcl-2 and increased expression of the multi-drug resistant gene. Traditional chemotherapeutic agents are streptozotocin in combination with 5-fluorouracil or doxorubicin, or to some extent dacarbazine. Temozolomide, capecitabine and oxaliplatin, as monoagents or in combination therapy, show efficacy in phase II trials. Patients with poorly differentiated neuroendocrine tumor, regardless of the primary tumor localization, are candidates for cisplatin and etoposide chemotherapy regimen. Peptide receptor radionuclide therapy is reported to be an effective treatment option for patients with good performance status and high somatostatin-receptor scintigraphy uptake as well as without major liver involvement. Basic fibroblast growth factor, vascular endothelial growth factor, platelet-derived growth factor, transforming growth factor alpha and beta, insulin-like growth factor type 1, epidermal growth factor, stem cell factor (c-kit), and corresponding receptors have been shown to be expressed in Neuroendocrine tumors. Current phase II-III clinical trials with molecular-targeted therapies revealed promising agents such as everolimus (RAD001), an oral mTOR inhibitor, and sunitinib malate (SU-11248), an oral multitargeted tyrosine kinase inhibitor against vascular endothelial growth factor receptors, platelet-derived growth factor receptors, c-kit receptors, glial cell linederived neurotrophic factor, and FMS-like tyrosine kinase-3 (Flt 3), which were approved for the treatment of advanced pancreatic neuroendocrine tumors. Ongoing clinical trials with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, will further define the role of angiogenesis inhibitors in advanced intestinal neuroendocrine tumors. Various further novel strategies of targeted therapy and microRNA-regulated pathways in neuroendocrine tumors are under development.